mmg_233_2013_genetics_genomicswikiaorg-20200214-history
Depression: A Genome-Wide Association Study
Depressive episodes are characteristic presentations in a myriad of mood disorders including major depressive disorder, dysthymic disorder, and Bipolar disorder types 1 and 2 (1,4). A depressive episode is defined by the fourth edition of the Diagnostic and Statistical Manual (DSM-IV) as "a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly all activities (4)" and the clinical presentation of at least four additional symptoms from the following list (4): #Changes in appetite or weight #Psychomotor agitation or retardation #Insomnia or hypersomnia nearly every day #Fatigue or loss of energy #Feelings of worthlessness or excessive or inappropriate guilt #Difficulty thinking, concentrating or making decisions #Recurrent thoughts of death or suicidal idealization, plans or attempts Depressed mood is also a key clinical component of many psychiatric, neurological, and psychosomatic syndromes (1). Depression is closely associated with neuroticism, a key component of the five fundamental personality traits as described by psychologists. Neuroticism is a multifaceted personality trait that indicates a propensity to experience an expansive range of negative emotions including depression, anxiety, and hostility. Several comprehensive, genetically-informed studies have indicated that neuroticism shares approximately 50% of its genetic liability with major depression, meaning that those with neurotic tendencies are predisposed to depressive illness. It is quite possible that neuroticism is the common denominator underlining certain psychiatric comorbidities. Mood disorders (of which depressive symptoms are a key component) are one of the leading causes of morbidity and disability internationally (1). The European Study of the Epidemiology of Mental Disorders (ESEMeD), which was completed in 2003, estimates lifetime prevalence of major depressive episodes to be approximately 17% among female European populations and 9.4% among male European populations. Regarding major depression in the United States, the National Comorbidity Survey-Replication (NCS-R) recently reported the lifetime prevalence of major depression to be about 16.2%. The NCS-R US study also reports a statistically significant correlation between the development of major depressive disorder and various sociodemographic factors such as age, marital status, employment and income levels (2). This finding affirms the existing paradigm that most psychological disorders, including major depressive disorder, arise from a variety of genetic, epigenetic and environmental factors. Given its wide prevalence, it should come as no surprise that major depression represents a huge economic burden in modern society (2). It is thus imperative that we learn all we can about depression so that we may someday apply this knowledge to combat this insidious disorder. By identifying the genetic variants that underline a predisposition to depressive illness, we can better elucidate the biological pathways involved. GWA Study In 2010, Antonio Terracciano and several of his associates at Florida State University published the results of the "first GWA study for the depression facet of personality (1)" in the journal of Biological Psychiatry. Antonio and his fellow researchers conducted personality inventories and collected genomic data from 2 separate populations: 6,148 individuals from Sardinia, Italy and 839 individuals of European ancestry from Baltimore, USA. Sardinia, Italy was selected as this particular area is known to harbor a founder population. Such a population descends from only a few ancestral lines and has high levels of genetic homogeneity, a trait that greatly increases the statistical power of GWAS. Individuals within the Baltimore, Maryland faction of the study are actually participants in a currently ongoing, multidisciplinary study (The Baltimore Longitudinal Study of Aging). Only participants of European ancestry were sampled in Baltimore in an attempt to reduce population stratification biases. In both of these populations, the trait depression was analyzed using the "English and Italian versions of the Revised NEO Personality Inventory (1)". Genomic analysis was preformed using the 500K Illumina platform and the 10K or 500K Affymetrix Mapping Array Sets in Baltimore and Sardinia, respectively. Due to the high level of Genetic homogeneity in the Sardinia population, data from the Affymetrix 500K platform was used to infer the missing SNP information of children or siblings genotyped with the Affymetrix 10K platform. Unfortunately, statistical analysis yielded no statistically significant findings (p < 5 x 10^-8). The 25 SNPs found to have the lowest p values can be found in the image opposite. Discussion The statistical meta-analysis preformed, in which data from both the Sardinia and Baltimore samples were combined, identified rs12912233 as the SNP with the lowest p value (p= 6 x 10^-7). This SNP, as well as 3 other SNPs identified on the table opposite, falls on chromosome 15 within a RORA gene (retinoic acid receptor-related orphan receptor alpha) intron. The RORA gene is a member of the NR1 superfamily of nuclear hormone receptors (1, 3). The exact function of the RORA gene is yet to deduced, though it is known to up-regulate gene expression in response to certain hormonal signals and its deletion has resulted in severe cerebellar ataxia due a deficit of functional Purkinje cells in mouse models (1, 3). New, novel evidence suggests that the RORA gene plays a vital role in immunity and may of integral importance to the establishment of mammalian circadian rhythms. Multiple animal models, GWAS, and linkage studies agree that the RORA gene likely linked to bipolar disorder and a recent Swedish Study also identified specific RORA SNPs to be associated with clinical depression. All of this compiled evidence together with the results of Terracciano's GWAS supports the role of RORA gene in trait depression (1 ). Terracciano and his colleagues considered the association between trait depression and the intronic SNP rs17864092 (p= 5.5 x 10^-6) within the metabotropic glutamate type 8 receptor gene (GRM8) to be the most biologically plausible finding. Glutamate is an essential excitatory neurotransmitter within the central nervous system that is involved in a plethora of neurological functions and has been implicated in multiple neuropathologies including Alzheimer's disease and addiction. Glutamate receptor type 8 is a group III metabotropic glutamate receptor known to participate in presynaptic glutamate release inhibition. Group III metabotropic glutamate receptors modulate glutamate levels within the central nervous system, an essential task as excessive levels of synaptic glutamate are know to have excitotoxic effects that incite cellular damage, neuronal atrophy and neuron loss. Burgeoning bodies of evidence have also suggested that the glutamatergic system is intimately involved in the development of certain neuropsychiatric disorders including anxiety and substance abuse. At this particular genetic locus, higher rates of depression were observed among those with a cytosine residue rather than a thymine pyrimidine residue. Terracciano and his team interpreted all of these past bodies of evidence and their own results as an indication that certain GRM8 genotypes represent alternations to the glutamate neurotransmission system and may predispose one to depression or other psychiatric disorders. (1 ). While these results may be fascinating, Terracciano and his fellow publishers caution readers that the genetic variants identified in their study represent only a small proportion (<1%) of the variance found within the trait depression and that additional genetic and epigenetic studies will be needed to adequately discern the neurophysiology of depression. References 1. Genome-Wide Association Scan of Trait Depression 2. Economic burden of depression on society 3. GeneCards 4. DSM-IV online